What is the evidence to support prophylactic anticoagulation in patients with nephrotic syndrome?

Nephrotic syndrome classically presents with heavy proteinuria (>3.5 g per day), hypoalbuminemia, edema, and hyperlipidemia. Damage to the glomerular basement membrane results in the loss of either charge or size selectivity, which then results in the leakage of glomerular proteins such as albumin, clotting factors, and immunoglobulins.[1] The heavy proteinuria seen in affected patients leads to a series of clinically important sequelae, including sodium retention, hyperlipidemia, greater susceptibility to infection, and a higher risk of both venous thromboembolism (VTE) and arterial thromboembolism (ATE).

The predisposition to a hypercoagulable state in nephrotic syndrome results from the urinary loss of clotting inhibitors such as antithrombin III and plasminogen. Hypercoagulability, in turn, can lead to a variety of complications including pulmonary embolism, renal vein thrombosis, and recurrent miscarriages. The incidence of both venous and arterial thrombosis is much higher in patients with nephrotic syndrome than in the general population. Mahmoodi and colleagues’ retrospective study of 298 patients with nephrotic syndrome followed for 10 years found a low absolute risk of venous and arterial thromboses: 1.02% and 1.48% per year, respectively.[2] These patients had approximately 8 times higher risk than the general population (matched for age and sex). The authors also found that the risk of venous and arterial thrombosis is highest in the first 6 months after diagnosis.[2-4] The risk of thrombosis varies with the underlying cause of nephrotic syndrome. Risk of these events is highest in membranous nephropathy, followed by membranoproliferative glomerulonephritis and minimal change disease.[5,6] While minimal change disease frequently responds to treatment with corticosteroids, membranous nephropathy is more difficult to treat and therefore more likely to lead to thrombosis.

Renal vein thrombosis typically presents with flank pain, gross hematuria, and loss of renal function, while pulmonary embolus usually presents with dyspnea, pleuritic chest pain, and tachypnea. A surprising number of patients with nephrotic syndrome who experience thromboembolic events present without any symptoms at all. Only one-tenth of patients with renal vein thrombosis and one-third of patients with pulmonary emboli are symptomatic.[5] With regard to renal vein thrombosis, Chugh and colleagues noted that because the development of venous occlusion is often slow and incomplete in patients with nephrotic syndrome, the clinical features of thrombosis are not easily distinguished from the primary renal disease.[6]

The overall risk of ATE in patients with nephrotic syndrome is related to both the glomerular filtration rate and the classic risk factors for atherosclerosis.[2] Increased risk of VTE, in contrast, is generally associated with high rates of proteinuria, low serum albumin levels, high fibrinogen levels, low antithrombin III levels, and hypovolemia.[7] Unfortunately, these are relatively unreliable predictors of patient outcomes. That potentially fatal thrombotic events can be clinically silent in nephrotic patients has important implications for treatment. Given that the incidence of thromboembolic complications in these patients is higher than in the general population, anticoagulant prophylaxis must be considered.

The likelihood of benefit from prophylactic anticoagulation depends on both the possibility of future thrombotic events, as discussed above, and the risks associated with anti-coagulation, such as intracranial hemorrhage and gastrointestinal bleeds. Unfortunately, data on prophylactic therapy in the nephrotic syndrome are seriously limited; there are no firm recommendations one way or another regarding anticoagulation. The decision to treat prophylactically must therefore be individualized, based on risk factors and prior history.

In circumstances where a patient has demonstrated a previous tendency towards hypercoagulability, such as previous pulmonary emboli in case 1 above, prophylactic anticoagulation would likely be warranted. In this case the benefit of anticoagulation outweighs the risk, particularly in the first 6 months after diagnosis when the risk of thromboembolism is highest. Patients with massive amounts of proteinuria and very low albumin are at especially high risk of VTE, and in these cases prophylactic anticoagulation should probably be given.

The patient in case 2 has milder disease and no history of thrombosis. Many physicians favor a more conservative approach to prophylaxis in this setting.* The risks of chronic anticoagulation frequently outweigh the benefits. In addition, while nephrotic syndrome predisposes to a hypercoagulable state, the risk of thrombosis is not necessarily lowered by anticoagulation. For example, the loss of antithrombin III in the urine contributes to the risk of hypercoagulability, but it also decreases the effectiveness of heparin. While this patient’s venous insufficiency increases the likelihood of deep vein thrombosis, chronic anticoagulation in a patient with no history of hypercoagulability seems unnecessary. That being said, no studies have addressed this issue and therefore practice will vary considerably.

The lack of evidence to support or refute the administration of prophylactic anticoagulation in patients with nephrotic syndrome means that the decision to treat prophylactically must be made on a case-to-case basis. Special consideration should be given to patients with a demonstrated history of hypercoagulability and to those with known hypercoagulable states. In addition, the literature suggests that patients should be monitored closely in the first 6 months after diagnosis for evidence of thrombosis. In all cases the risk of hemorrhage should be weighed heavily against the potential benefits of anticoagulation.

* Many thanks to Drs. Jerome Lowenstein, Gregory Mints, Manish Ponda, and Joseph Weisstuch for their input on this topic.

Commentary by Dr. Jerome Lowenstein

Jennifer Mulliken makes a reasonable argument for individualizing the decision to anticoagulate, as there are no appropriate trials comparing conservative management with anticoagulation. Unfortunately, individualization is not very easy when there are no good markers of high risk and there is no good evidence of the effect of anticoagulation in renal vein thrombosis.

Jennifer Mulliken is a 3rd year medical student at NYU School of Medicine

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